A Novel Leukotriene Antagonist, ONO-1078, Inhibits and Reverses Human Bronchial Contraction Induced by Leukotrienes C4and D4and AntigenIn Vitro

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Abstract
ONO-1078, 4-oxo-8(-)[p-(4-phenylbutyloxy)benzoylamino]-2-(tetrazol-5-y l)-4H-1-benzopyran hemihydrate, is a novel compound that has been shown to be a leukotrienes C4 and D4 (LTC4, LTD4) antagonist in the guinea pig airways. We studied the ability of ONO-1078 to inhibit and reverse the contraction of isolated human bronchus induced by LTC4, LTD4, and antigen. The human bronchial tissues were prepared from patients undergoing surgery for lung cancer, and they were placed in organ baths. ONO-1078 (10(-8) to 10(-6) M) produced a concentration-dependent inhibition of LTC4 and LTD4 concentration-response curves. In the presence of l-serine borate complex, which inhibits the conversion of LTC4 to LTD4 by gamma-glutamyl transpeptidase, ONO-1078 significantly inhibited the LTC4-induced contraction, suggesting that ONO-1078 is an antagonist of both LTC4 and LTD4. ONO-1078 (10(-6) M) also significantly reversed an ongoing contraction induced by LTC4 (10(-7) M). The inhibitory effect of ONO-1078 on LTC4-induced contraction was at least 100 times more potent than that of FPL 55712, the first discovered LTC4 and LTD4 antagonist. To study the effect of ONO-1078 on the contraction induced by antigen challenge, bronchial tissues were incubated for 2 h with serum of high specific IgE against house dust from an asthmatic patient. House dust antigen was added to the sensitized bronchial tissues after incubation with ONO-1078 (10(-6) M) or histamine H1 antagonist pyrilamine (10(-6) M), either alone or in combination.(ABSTRACT TRUNCATED AT 250 WORDS)